The long-term objective is to gain knowledge of the rival and host determinants contributing to measles and vaccine-induced immunosuppression. Measles virus (MV) infects monocytes/macrophages and induces suppression of interleukin-12 production important for cellular immunity. We hypothesize that immunosuppression is triggered by interaction between the MV hemagglutinin (H) protein and human cell receptor CD46 which sequesters cellular factors important for macrophage activation. The H proteins of laboratory and vaccine MV strains induce CD46 downregulation from the infected cell surface, whereas the wild-type MV H proteins do not cause CD46 downregulation. We hypothesize that this difference allows wild-type MV to interact continuously with CD46 to cause prolonged immunosuppression. In support of these hypotheses, we have identified a tyrosine-containing sequence in the CD46 cytoplasmic domain essential for CD46 downregulation. This CD46 sequence resembles known "tyrosine activation motifs" recognized by Src family kinases. Mitogen treatment of macrophages induces a transient increase in cellular kinase activities which associate with the CD46 cytoplasmic domain and cause tyrosine phosphorylation in vitro. Multiple CD46-associated proteins also become phosphorylated. The roles of the MV H protein, CD46, and macrophage activation factors in measles/vaccine-induced immunosuppression must be clearly understood in order to design better vaccines or therapeutics against measles. Our Specific Aims are: 1. Characterize the eCD46 sequences which interact with mitogen-inducible macrophage kinases and identify those kinases. 2. Determine the roles of the CD46 sequences and macrophage kinases in MV-induced immunosuppression. 3. Define the amino acid residues in the MV H proteins of wild-type versus laboratory-adapted MV responsible for differential CD46 downregulation and possibly immunosuppression. We will achieve these aims by dissecting the interplay between MV, CD46, and cellular factors in vitro and in cultured mouse macrophages expressing human CD46 and mutant receptors.